Hydrogel-integrated exosome mimetics derived from osteogenically induced mesenchymal stem cells in spheroid culture enhance bone regeneration

Changlu Xu; Zhi Li; Minjee Kang; Yiqing Chen; Ruoyu Sheng; Tara Aghaloo; Min Lee

doi:10.1016/j.biomaterials.2025.123088

Hydrogel-integrated exosome mimetics derived from osteogenically induced mesenchymal stem cells in spheroid culture enhance bone regeneration

Biomaterials. 2025 Jan 3:317:123088. doi: 10.1016/j.biomaterials.2025.123088. Online ahead of print.

Authors

Changlu Xu¹, Zhi Li¹, Minjee Kang¹, Yiqing Chen², Ruoyu Sheng², Tara Aghaloo³, Min Lee⁴

Affiliations

¹ Division of Oral and Systemic Health Sciences, School of Dentistry, University of California, Los Angeles, CA, 90095, USA.
² Department of Bioengineering, University of California, Riverside, CA, 92521, USA.
³ Division of Diagnostic and Surgical Sciences, School of Dentistry, University of California, Los Angeles, CA, 90095, USA. Electronic address: [email protected].
⁴ Division of Oral and Systemic Health Sciences, School of Dentistry, University of California, Los Angeles, CA, 90095, USA; Department of Bioengineering, University of California, Los Angeles, CA, 90095, USA. Electronic address: [email protected].

PMID: 39756271
DOI: 10.1016/j.biomaterials.2025.123088

Abstract

Exosomes derived from mesenchymal stem cells (MSCs) offer a promising alternative to traditional cell-based therapies for tissue repair by mitigating risks associated with the transplantation of living cells. However, insufficient osteogenic capacity of exosomes diminishes their potential in bone tissue regeneration. Here, we report novel osteogenically induced exosome mimetics (EMs) integrated into injectable hydrogel carriers for improved bone regeneration. EMs were produced by a serial extrusion of MSCs cultured as spheroids during osteogenic induction. The prepared EMs were chemically anchored on a self-healing hydrogel assembled by guanidinylated hyaluronic acid and silica-rich nanoclays for sustained release of EMs. The administration of hydrogel-integrated EMs into mouse calvarial defects resulted in robust bone tissue regeneration. miRNA sequencing revealed altered expression of specific miRNAs in the EMs related to Wnt/β-catenin and Notch signaling pathways. Our study provides new insights into the development of advanced exosome-based cell-free therapies for bone tissue engineering.

Keywords: Bone regeneration; Exosome mimetics; MSC spheroids; Self-healing hydrogel; miRNAs.